Benzothiazine dioxides as lipid regulating agents

ABSTRACT

Certain 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide1,1-dioxide and 3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1dioxide compounds effective as lipid regulating agents are disclosed.

United States Patent Lombardino et al.

[ 1 July 4,1972

[54] BENZOTHIAZINE DIOXIDES AS LIPID REGULATING AGENTS [72] lnventors: Joseph G. Lombardino, Niantic; Gerald F.

Holland, Old Lyme, both of Conn.

[73] Assignee: Pfizer Inc.

[22] Filed: June 9, 1969 [21] Appl. No.: 831,768

[52] US. Cl ..424/246 [51] Int. Cl. 1 ..A6lk 27/00 [58] Field of Search ..424/246; 260/243 Primary Examiner-Albert T. Meyers Assistant Examiner-Allen J. Robinson Attorney-Connolly and Hutz [57] ABSTRACT Certain 3,4-dihydr0-4-ox0-2H-l,2-benzothiazine-3-carboxamide-l,l-dioxide and 3-oxo-2H-l ,Z-benzothiazine-4-carboxamide-l,l-di0xide compounds effective as lipid regulating agents are disclosed.

36 Claims, N0 Drawings BEN ZOTIIIAZINE DIOXIDES AS LIPID REGULATING AGENTS BACKGROUND OF THE INVENTION This invention relates generally to a method of regulating lipid metabolism in humans. More particularly, it is concerned with 2H-l,2-benzothiazine-l,l-dioxide derivatives, and with the effectiveness of said derivatives as lipid regulating agents.

What is meant by the term regulating lipid metabolism" is the ability to depress triglycerides, free fatty acids, cholesterol, lipoprotiens, phospholipids, etc. in human and animal blood.

SUMMARY OF THE INVENTION In accordance with the present invention, it has been found that various novel 2I-I-l,2-benzothiazine-l,l-dioxide compounds are surprisingly useful when employed in the field of drug therapy as lipid regulating agents. The novel compounds of this invention are 2H-1,2-benzothiazine-l,l-dioxides of the formula:

and the base salts thereof with pharmacologically acceptable cations, wherein X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, alkyl and alkoxy having from one to five carbon atoms and trifiuoromethyl; R is a member selected from the group consisting of OR, and NI-IR wherein R is alkyl having from one to l2 carbon atoms or phenylalkyl having up to three carbon atoms in the alkyl moiety, and R is chosen from the group consisting of hydrogen, alkyl having from one to eight carbon atoms; alkenyl having up to six carbon atoms, cycloalkyl having up to eight carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety, nitrophenyl, naphthyl, phenyl, pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5- methyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-chloro-2-pyridyl, 5-nitro-2-pyridyl, 3-hydroxy-2-pyridyl, 5- carboxamido-Z-pyridyl, 2-pyrazinyl, 2 -pyrimidyl, 4,5- dimethyl-Z-pyrimidyl, 4-pyrimidyl, 5-methyl-3-pyridazinyl, 6- methoxy-3-pyridazinyl, l-phenyl-3-pyrazolonyl, 2-thiazolyl, 4- methyl-Z-thiazolyl, 4,5-dimethyl-2-thiazolyl, 4-phenyI-2- thiazolyl, 5-bromo-2-thiazolyl, 3-isothiazolyl, 2- benzothiazolyl, 6-methyl-2-benzothiazolyl, 4-chloro-2- benzothiazolyl, 6-bromo2-benzothiazolyl, 5-chloro-2- benzoxazolyl, 1,3,4-thiadiazolyl, S-methyll ,3,4-thiadiazolyl, 1,2,4-thiazolyl, 6-phenyl-l,2,4-triazolyl, 7-indazolyl and monoand di-substituted phenyl wherein each substituent is halogen, hydroxy, alkoxy and thioalkoxy having up to three carbon atoms, alkyl having up to four carbon atoms, trifluoromethyl, acetyl, methylsulfinyl or methylsulfonyl; R is a member selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, alkenyl having up to four carbon atoms and phenylalkyl having up to three carbon atoms in the alkyl moiety; and Z is oxygen or sulfur, except when R is OR when it is oxygen.

Of especial interest in this connection are those compounds where and Y are hydrogen, Z is oxygen, R is -NI-IR wherein R is a member selected from the group consisting of phenyl, nitrophenyl, pyridyl, 6-methyl-2-pyridyl, 2-pyrazinyl, 2-pyrmidyl, 2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 3-isothiazolyl, 2- benzothiazolyl, 7-indazolyl and monoand di-substituted phenyl wherein each substituent is halogen, hydroxy, alkoxy and thioalkoxy having up to three carbon atoms, alkyl having up to four carbon atoms, trifluoromethyl, acetyl, methylsulfinyl or methylsulfonyl; R having from one to six carbon atoms, and Z is oxygen or sulfur. Typical member compounds embraced by this invention include 3,4-dihydro2-methyl-4-oxo- 2H- 1 ,2-benzothiazine-3-carboxanilide-l l -dioxide, 3 '-chloro- 3,4-dihydro-2-methyl-4-oxo-2H- l ,2-benzothiazine-3carboxanilidel l -dioxide, 2-methoxy-3,4-dihydro-2-methyl-4-ox0- 2H- l ,2-benzothiazine-3-carboxanilide-l ,l-dioxide, 3 trifluoromethyl-3,4-dihydro-2-methyl-4oxo-2H- l ,2- benzothiazine-3-carboxanilidel l -dioxide, N-( 2-thiazolyl 3,4-dihydro- 2-methyl-4-oxo-2H- 1 ,2-benzothiazine-3-carboxamidel l-dioxide, N-( Z-pyridyl)-3,4-dihydro-2-methyl-4- oxo-2H-l,2-benzothiazine-3-carboxamide-1,1-dioxide, N-( 6- methyl-2-pyridyl )-3,4-dihydro-4-oxo-2H-l ,2-benzothiazine-3- carboxamide-1,l-dioxide, 2 '4 '-dichloro-3 ,4-dihydro-2- methyl-3-oxo-2H-1,2-benzothiazine-4- carboxanilidel ,ldioxide, 4'-bromo-3 ,4-dihydro-2-methyl-3-oxo-2H- l ,2- benzothiazine-4-carboxanilide-1,1-dioxide, 2 '-chloro- 3 ,4- dihydro-2-methyl-3-oxo-2H-1,2-benzothaizine-4-carboxanilidel ,l-dioxide and 4-methylsulfonyl-3,4-dihydro-2-methyl- 3-oxo-2I-I-l,2-benzothiazine-4-carboxanilide-1,l-dioxide. It is to be understood that many of these compounds exist in the enolic form (i.e. they are tautomeric and can be 4-hydroxy or 3-hydroxy, as the case may be).

In addition, the carboxylate esters of this invention, where R.

is OR as previously defined, are extremely useful as intermediates for preparing the aforementioned carboxamide compounds via the conventional ammonolysis route using the appropriate amines. Typical and preferred esters of this invention, for use in the present connection, include those carboxylates where X and Y are each hydrogen, 2 is oxygen, R is OR wherein R is alkyl having from one to twelve carbon atoms, and R is a member selected from the group consisting of hydrogen and alkyl having from one to six carbon atoms, such as, for example, methyl-3,4-dihydro-2-methyl-4-oxo-2H-l,2- benzothiazine-3-carboxylate-1,1-dioxide and ethyl-3,4- dihydro-Z-methyl- 3-oxo-2I-I-1,2-benzothiazine-4-carboxylate-1,1-dioxide. These compounds also possess lipid regulating activity.

DETAILED DESCRIPTION OF THE INVENTION The methods of preparation and chemical properties of the benzothiazine dioxides of this invention are described in Ser. No. 767,594, filed Aug. 27, 1968, now US. Pat. No. 3,591,584. Included within the scope of the designated compounds are the pharmaceutically-acceptable acid addition salts.

The benzothiazine dioxides of this invention can be administered either alone or preferably in combination with a pharmaceutically-acceptable carrier. They may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions or solutions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or filters, sterile aqueous media and various nontoxic organic solvents. Moreover, the oral pharmaceutical compositions of this invention may be suitably sweetened and flavored by means of various agents of the type commonly employed for just such a purpose.

For purposes of parenteral administration, solutions of suspensions of of the herein described benzothiazine dioxides in sesame or peanut oil or in aqueous propylene glycol solutions can be employed, as well as sterile aqueous solutions of the corresponding water-soluble addition salts previously enumerated. These particular solutions are especially suited for intramuscular and subcutaneous injection purposes. The aqueous solutions, including those of the addition salts dissolved in pure distilled water, are additionally useful for intravenous injection purposes provided that their pH be properly adjusted before hand. Such solutions should also be suitable buffered, if necessary, and the liquid diluent first rendered isotonic with sufi'icient saline or glucose.

When administered to humans orally or parenterally, the effective average daily dose is suitably between about 0.5 g. per day and about 3 g. per day. The dosage can be taken at one time or divided dosages can be taken at different times during the day. On a body weight basis, a dosage of about 73 to about 440 mg./kg. per day is appropriate.

The physician will determine the dosage which will be most suitable for an individual patient and it will with the age, the weight, and response of the particular patient. The above dosages are exemplary of the average host. There can, of course, be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The term lipids is used here in the broad sense, covering triglycerides, cholesterol, phospholipids and free fatty acids. It is generally accepted that abnormalities in lipid metabolism, frequently indicated by elevated blood lipid levels, are closely associated with atherosclerosis, with cardiovascular disease, and with derangements of carbohydrate metabolism, e.g. diabetes. Drugs which will lower lipid levels can therefore be expected to be useful in the treatment of these diseases, and of others in which lipid metabolism is abnormal.

The products of this invention are tested in vivo for hypolipemic activity by measuring their ability to lower the blood lipid level of mammals. This property can be demonstrated in rats. Groups, each comprising 4 animals, normal Sprague-Dawley (Charles River) male rats weighing from l60-220 grams, are fed rat chow containing 0.25 percent of the compounds described herein for two overnight feeding periods. On the morning of the third day the animals are anesthetized and bled from the abdominal aorta. The total plasma cholesterol is then determined by the method of 1.]. Carr and LI. Drekter reported in Clin. Chem., 2, 353 (I956). The plasma cholesterol level of the treated animals is found to be significantly reduced when compared to animals not receiving the test compound,

The following examples are provided by way of illustration, and should not be interpreted as limiting the invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:

l,2-dihydro-4-hydroxy-2-methyll ,Z-benzothiazine 3(P-tolylcarboxanilide)-l,l-dioxide 50 Sodium citrate 25 Alginic acid 10 Polyvinylpyrrolidone Magnesium stearate 5 EXAMPLE ll A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:

benzothiazine-4-carboxanilidel l dioxide 50 Calcium carbonate 20 Polyethylene glycol, average molecular weight 4000 30 The dried solid mixture so prepared is then throughly agitated so as to obtain a powdered product that is completely uniform. Soft elastic and hardfilled gelatin capsules containing this pharmaceutical composition are then prepared, employing a sufficient quantity of material in each case so as to provide each capsule with 190 mg. of the active ingredient.

EXAMPLE lll Groups, each comprising 4 animals, of normal Sprague- Dawley (Charles River) male rats weighing from -220 grams are fed rat chow containing 0.25 percent of the test compounds for two overnight feeding periods. On the morning of the third day the animals are anesthetized and bled from the abdominal aorta. The total plasma cholesterol is then determined by the method of 1.1. Carr and U. Drekter reported in Clin. Chem., 2, 353 (1956). The following results are obtained:

Compound 71 Cholesterol Fall l,2-dihydro-4-hydroxy-2-methyll ,2- benzothiazine-3(p-toluidide l l -dioxide 3,4'-dichloro-4-hydroxy-Z-methyl-ZH- l,2benzothiazine-S-carboxanilidel l dioxide 2-chIoro-4-hydroxy-Z-methyl-ZH- l ,2-

benzothiazine-3-carboxanilidel ldioxide 4'-bromo-4hydroxy-2-methyl-2H-1,2- benzothiazine-3-carboxanilidel l dioxide 2-methyl-3-chloro-4hydroxy-2H-l,2

benzothiazine-3-o-toluidide l l -dioxide -carboxa- 4-acetyl-4-hydroxy-2-methyl-2H- l ,2-

benzothiazine-carboxanilidel l -dioxide 2,2,5'-trimethyl-4'-nitro-4-hydroxy- 2H- 1 ,2-benzothiazine-3-carboxanilide-l, l dioxide 2',4',5-trichloro-4-hydroxy-2-methyl-2H-1,2- benzothiazine-3-carboxanilide-l l -dioxide N-( S-methyll ,3,4-thiadiazol-2-yl )-4- hydroxy-Z-methyl-ZH- l ,Z-benzothiazine- 3-carboxamidel ldioxide N(4-methyl-2-pyridyl)-4-hydroxy-2- methyl-2H- l ,2benzothia2ine-3-carboxzmide-l,l-dioxide N-(S-bromo-Z-pyridyl)-4-hydroxy-2- methyl-2H- l ,2benzothiazine-3-carboxamide-l,l-dioxide 4-hydroxy-2-methyl-N-[6-methyl2-benzo thiazolyl )-2H- l ,2-ben2othiazine-3- carboxamidel l -dioxide N-( 6-bromo-2benzothiazolyl )-4-hydroxy 2-methyl-2H- l ,2-benzothiazine-3-carboxamidel l-dioxide 3,5-dihydro-2-methyl3-oxo-2H- l ,2-benzothiazine-4-(p-anisidide)-l l -dioxide 3,4-dihydro-2methyl-3-oxo 2H- l ,Z-benzothiazine-4-( p-toluidide l l-dioxide 3,4dihydro-2-methyl-N-( l-naphthyl)-3- oxo-ZH- l ,2-benzothiazine-4-carboxamide-l,l-dioxide 3,4-dihydro-4'ethoxy-2-methyl3-oxo- 2H- 1 ,2-benzothiazine-4-carboxanilidel, l -dioxide 3,4'-dichloro-3,4-dihydro-2methyl-3- oxo-ZH- l ,2-benzothiazine-4-carboxanilide-l,l-dioxide 2-benzyl-4'-chloro-3,4-dihydro-3-oxo- 2H- 1 ,2-benzothiazine-4-carboxanilidel, l -dioxide 3,4-dihydro-2-methyl-3'-trifluoromethyl- 3-oxo-2H l ,2-benzothiazine-4-carboxanilidel l -dioxide 2-benzyl-2',4'-dichloro-3,4-dihydro-3- oxo-ZH- l ,2-benzothiazine-4-carboxanilidel l dioxide 3'-chloro-3,4-dihydro-2,4'-dimethyl-3- oxol ,2-benzothiazine-4-carboxanilidel,1-dioxide 4'-acetyl-3,4'dihydro-2-methyl-3-oxo- 2H-l ,2'benzothiazine-4-carboxanilidel,l-dioxide 4-hydroxy-2-methyll ,2-benzothiazine-3- thiocarboxanilidel l -dioxide 4'-bromo-3,4-dihydro-2,7-dimethyl-3- oxol ,2-benzothiazine-4-carboxanilidel, l -dioxide The remaining compounds of this invention cause a drop in plasma cholesterol levels in a comparable percentage range.

What is claimed is:

l. A method of lowering lipid levels in a human which comprises the oral or parenteral administration to a human in need of said treatment an effective amount for lowering lipid levels of a compound selected from the group consisting of or the base salts thereof with pharmacologically-acceptable cations, wherein X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, alkyl and alkoxy having from one to five carbon atoms, and trifluoromethyl; R is a member selected from the group consisting of OR, and Nl-lR wherein R is alkyl having from one to 12 carbon atoms or phenylalkyl having up to three carbon atoms in the alkyl moiety, and R is chosen from the group consisting of hydrogen, alkyl having from one to eight carbon atoms, alkenyl having up to six carbon atoms, cycloalkyl having up to eight carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl, nitrophenyl, naphthyl, pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5- methyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-chloro-2-pyridyl, 5-bromo-2-pyridyl, 5-nitro-2-pyridyl, 3- hydroxy-2-pyridyl, 5-carboxamido-2-pyridyl, 2-pyrazinyl, 2- pyrimidyl, 4,5-dimethyl-2-pyrimidyl, 4-pyrimidyl, 5-methyl-3- pyridazinyl, 6-methoxy-3-pyridazinyl, 1-phenyl-3-pyrazolonyl, 2-thiazolyl, 4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, 5- brorno-Z-thiazolyl, 4,5-dimethyl-2-thiazolyl, 3-isothiazoyl, 2- benzothiazolyl, 6-methyl-2-benzothiazolyl, 4 chloro-2- benzothiazolyl, 6-bromo-2-benzothiazolyl, 5-chloro-2- benzoxazolyl, 1,3,4-thiadiazolyl, S-methyl-l ,3,4-thiadiazolyl, 1,2,4-triazolyl, 6-phenyl-I,2,4-triazolyl, 7-indazolyl, monoand di-substituted phenyl wherein each substitutent is halogen, hydroxy, alkoxy or thioalkoxy having up to three carbon atoms, alkyl having up to four carbon atoms, trifluoromethyl, acetyl, methylsulfinyl or methylsulfonyl; R is a member selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, alkenyl having up to four carbon atoms and phenylalkyl having up to three carbon atoms in the alkyl moiety; and Z is oxygen or sulfur, ex-

cept when R is ---OR when it is oxygen.

2. The method of claim 1 wherein said compound is a 3,4- dihydro-4-oxo-2H-l ,2-benzothiazine-3-carboxamide-l,1- dioxide having the first formula wherein R is NHR 3. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2H-1 ,2-benzothiazine-3-carboxamidel l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is phenyl and R is alkyl of from one to six carbon atoms.

4 The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2H-l,2benzothiazine3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, 2 is sulfur, R is phenyl and R is alkyl of from one to six carbon atoms.

5. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2l-ll ,2benzothiazine-3-carboxamidel l -dioxide wherein X and Y are each hydrogen, Z is oxygen, R is chlorophenyl and R is alkyl of from one to six carbon atoms.

6. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2l-l1,2-benzothiazine-3-carboxamide-l,ldioxide wherein X and Y are each hydrogen, 2 is oxygen, R is phenylalkyl having up to three carbon atoms in the alkyl moiety and R, is alkyl of from one to six carbon atoms.

7. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2l-l-l,2-benzothiazine-3-carboxamide-1,1- dioxide wherein X and Y are each hydrogen, Z is oxygen, R is alkenyl having up to six carbon atoms and R is alkyl of from one to six carbon atoms.

8. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2l-l-l,2-benzothiazine-3-carboxamide-1,1- dioxide wherein Xand Y are each hydrogen, Z is oxygen, R is cycloalkyl having up to eight carbon atoms and R is alkyl of from one to six carbon atoms.

9. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2H- l ,2-benzothiazine'3-carboxamidel l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is dichlorophenyl and R is alkyl of from one to six carbon atoms.

10. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2H- l ,2-benzothiazine-3-carboxamidel l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is chlorophenyl and R is hydrogen.

11. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2l-ll ,2-benzothiazine-3-carboxamidel l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is 2-thiazolyl and R is alkyl of from one to six carbon atoms.

12. The method of claim 2 wherein said compound is a 3,4- dihydro-4oxo-2H-l,2-benzothiazine-3-carboxamide-1,l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is pyridyl and R is alkyl of from one to six carbon atoms.

13. The method of claim 2 wherein said compound is a 3,4- dihydro-4-oxo-2H- l ,2-benzothiazine-3-carboxamidel l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is monomethyl Z-pyridyl and R is alkyl of from one to six carbon atoms.

14. The method of claim 1 wherein said compound is a 3,4- dihydro-4-oxo-2H- l ,2-benzothiazine-3-carboxylatel 1 -dioxide having the first formula wherein R is OR, and Z is oxygen.

15. The method of claim 14 wherein said compound is a 3 ,4-dihydro-4-oxo-2H- l ,2-benzothiazine-3-carboxylatel ldioxide wherein X and Y are each hydrogen, R is alkyl having from one to 12 carbon atoms and R is alkyl of from one to six carbon atoms. I I

16. The method of claim 14 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1 1 dioxide wherein X and Y are hydrogen, R is alkyl having from one to 12 carbon atoms and R is hydrogen.

17. The method of claim 1 wherein said compound is a 3,4- dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxamidel l dioxide having the second formula wherein R is NHR 18. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxamide-l ,ldioxide wherein X and Y are each hydrogen, Z is oxygen, R is phenyl and R is alkyl of from one to six carbon atoms.

19. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,Z-benzothiazine-4-carboxamide-l ,ldioxide wherein X and Y are each hydrogen, Z is oxygen, R is chlorophenyl and R is alkyl of from one to six carbon atoms.

20. The method of claim 17 wherein said compound is a 3 ,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxamide-l ,1- dioxide wherein X and Y are each hydrogen, Z is oxygen, R is pyridyl and R is alkyl of from one to six carbon atoms.

21. The method of claim 17 wherein said compound is a 3 ,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxamide-l ,ldioxide wherein X and Y are each hydrogen, 2 is oxygen, R is dichlorophenyl and R is alkyl having from one to six carbon atoms.

22. The method of claim 17 wherein said compound is a 3 ,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxamidel l dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is -bromophenyl and R is alkyl of from one to six carbon atoms.

23. The method of claim .17 wherein said compound is a 3 ,4-dihydro-3-oxo-2l-ll ,2-benzothiazine-4-carboxamidel l dioxide wherein X and Y are each hydrogen, Z is oxygen, R is naphthyl and R is alkyl of from one to six carbon atoms.

24. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-21-ll ,2-benzothiazine-4-carboxamidel ,1- dioxide wherein X and Y are each hydrogen, 2 is oxygen, R is alkyl having from one to eight carbon atoms and R is alkyl of from one to six carbon atoms.

25. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxamide-l l dioxide wherein X is hydrogen, Y is alkyl having from one to five carbon atoms, Z is oxygen, R is dichlorophenyl and R is alkyl of from one to six carbon atoms.

26. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-l ,2-benzothiazine-4-carboxamide-1,1- dioxide wherein X is hydrogen, Y is alkyl having from one to five carbon atoms, Z is oxygen, R is bromophenyl and R is alkyl of from one to six carbon atoms.

27. The method of claim 17 wherein said compound is a 3 ,4-dihydro-3-oxo-2H-l,2-benzothiazine-4-carboxamide-1,ldioxide wherein X and Y are each hydrogen, Z is oxygen, R is phenyl and R is phenylalkyl having up to three carbon atoms in the alkyl moiety.

28. The method of claim 17 wherein said compound is a 3,4-dihydro-3oxo-2l-l-l,2-benzothiazine-4-carboxamide-1,1- dioxide wherein X and Y are each hydrogen, Z is oxygen, R is 2-thiazolyl and R is alkyl of from one to six carbon atoms.

29. The method of claim 1 wherein said compound is a 3,4- dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxylatel l-dioxide having the second formula wherein R is OR and Z is oxygen.

30. The method of claim 29 wherein said compound is a 3 ,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4-carboxylatel ldioxide wherein X and Y are each hydrogen, R is alkyl having from one to 12 carbon atoms and R is alkyl of from one to six carbon atoms.

31. The method of claim 17 wherein said compound is 3,4- dihydro-4'-eth0xy-2-methyl-3-0x0-2Hl ,2-benzothiazine-4- carboxanilide -l,1-dioxide.

32. The method of claim 17 wherein said compound is 2- benzyl-4-chloro-3,4-dihydro-3-oxo-2H- l ,2-benzothiazine-4- carboxanilidel 1 -dioxide. 1

33. The method ofclaim 2 wherein said compound is 22 ',5' -trimethyl-4 -nitro-4-hydroxy-2H- l ,2-benzothiazine-3-carboxanilidel l -dioxide.

34. The method of claim 17 wherein said compound is 2- benzyl-2,4-dichloro-3,4-dihydro-3-oxo-2H- 1 ,2- benzothiazine-4-carboxanilidel l -dioxide.

35. The method of claim 2 wherein said compound is 4- hydroxy-2-methyl-N-( 6-methyl-2-benzothiazolyl )-2H- 1 ,2- benzothiazine-3-carboxamide-1,-l-dioxide.

36. The method of claim 2 wherein said compound is N-( 6- bromo-2-benzothiazolyl)-4-hydroxy-2-methyl-2H- l ,2- benzothiazine-3-carboxamidel l-dioxide. 

2. The method of claim 1 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide having the first formula wherein R is -NHR2.
 3. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is phenyl and R3 is alkyl of from one to six carbon atoms.
 4. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2benzothiazine3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is sulfur, R2 is phenyl and R3 is alkyl of from one to six carbon atoms.
 5. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is chlorophenyl and R3 is alkyl of from one to six carbon atoms.
 6. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is phenylalkyl having up to three carbon atoms in the alkyl moiety and R3 is alkyl of from one to six carbon atoms.
 7. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is alkenyl having up to six carbon atoms and R3 is alkyl of from one to six carbon atoms.
 8. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is cycloalkyl having up to eight carbon atoms and R3 is alkyl of from one to six carbon atoms.
 9. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is dichlorophenyl and R3 is alkyl of from one to six carbon atoms.
 10. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is chlorophenyl and R3 is hydrogen.
 11. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is 2-thiazolyl and R3 is alkyl of from one to six carbon atoms.
 12. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is pyridyl and R3 is alkyl of from one to six carbon atoms.
 13. The method of claim 2 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide wherein X and Y are each hyDrogen, Z is oxygen, R2 is monomethyl 2-pyridyl and R3 is alkyl of from one to six carbon atoms.
 14. The method of claim 1 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide having the first formula wherein R is OR1 and Z is oxygen.
 15. The method of claim 14 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide wherein X and Y are each hydrogen, R1 is alkyl having from one to 12 carbon atoms and R3 is alkyl of from one to six carbon atoms.
 16. The method of claim 14 wherein said compound is a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1dioxide wherein X and Y are hydrogen, R1 is alkyl having from one to 12 carbon atoms and R3 is hydrogen.
 17. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide having the second formula wherein R is -NHR2.
 18. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2is phenyl and R3 is alkyl of from one to six carbon atoms.
 19. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is chlorophenyl and R3 is alkyl of from one to six carbon atoms.
 20. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is pyridyl and R3 is alkyl of from one to six carbon atoms.
 21. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is dichlorophenyl and R3 is alkyl having from one to six carbon atoms.
 22. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is bromophenyl and R3 is alkyl of from one to six carbon atoms.
 23. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is naphthyl and R3 is alkyl of from one to six carbon atoms.
 24. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is alkyl having from one to eight carbon atoms and R3 is alkyl of from one to six carbon atoms.
 25. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X is hydrogen, Y is alkyl having from one to five carbon atoms, Z is oxygen, R2 is dichlorophenyl and R3 is alkyl of from one to six carbon atoms.
 26. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X is hydrogen, Y is alkyl having from one to five carbon atoms, Z is oxygen, R2 is bromophenyl and R3 is alkyl of from one to six carbon atoms.
 27. The method of claim 17 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is phenyl and R3 is phenylalkyl having up to three carbon atoms in the alkyl moiety.
 28. The method of claim 17 wherein said compound is a 3,4-dihydro-3oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide wherein X and Y are each hydrogen, Z is oxygen, R2 is 2-thiazolyl and R3 is alkyl of from one to six carbon atoms.
 29. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxylate-1,1-dioxide having the second formula wherein R is OR1 and Z is oxygen.
 30. The method of claim 29 wherein said compound is a 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxylate-1,1-dioxide wherein X and Y are each hydrogen, R1 is alkyl having from one to 12 carbon atoms and R3 is alkyl of from one to six carbon atoms.
 31. The method of claim 17 wherein said compound is 3,4-dihydro-4''-ethoxy-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide -1, 1-dioxide.
 32. The method of claim 17 wherein said compound is 2-benzyl-4''-chloro-3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1, 1-dioxide.
 33. The method of claim 2 wherein said compound is 2,2'',5''-trimethyl-4''-nitro-4-hydroxy-2H-1,2-benzothiazine-3-carboxanilide -1,1-dioxide.
 34. The method of claim 17 wherein said compound is 2-benzyl-2'', 4''-dichloro-3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,1 -dioxide.
 35. The method of claim 2 wherein said compound is 4-hydroxy-2-methyl-N-(6-methyl-2-benzothiazolyl)-2H-1,2-benzothiazine-3 -carboxamide-1,1-dioxide.
 36. The method of claim 2 wherein said compound is N-(6-bromo-2-benzothiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3 -carboxamide-1,1-dioxide. 